Project Summary: This grant application is in response to a request from the NIA funding opportunity announcement (FOA), which encourages exploratory/developmental research projects to accelerate the pace of development of novel therapeutics involving biologics, pharmacological and non-pharmacological approaches for preventing and treating key health issues affecting the elderly. The current proposal is based on our laboratory's development of the adenylyl cyclase type 5 (AC5) knock out (KO) mouse, which is a model for both longevity and healthful aging. The AC5 KO mouse lives a third longer than its wild type (WT). More importantly for clinical translation, the AC5 KO is protected against diabetes, obesity and cardiac disease and also improves exercise performance, all major factors required for healthful aging. It is obvious that clinical translation of this mechanism, AC5 inhibition, would be extremely important for the aging population. Accordingly, the goal of this proposal is to compare the effects of two known AC5 inhibitors, Ara Ade and PMC6, on the parameters of healthful aging noted above that are known to be protected in the AC5 KO mouse. Another key clinically relevant feature of these AC5 inhibitors is that they protect ischemic myocardium and reduce infarct size, even when administered after coronary artery reperfusion. This is key for clinical translation because when patients with myocardial infarction come to the emergency room, the first priority is to reperfuse the occluded coronary artery, leaving no time to administer a drug. Another aim is to develop a new AC5 inhibitor with minimal side effects that can be administered orally.